The present invention relates to lactam inhibitors of the enzyme Factor Xa which are useful as anticoagulants in the treatment of cardiovascular diseases associated with thromboses.
In accordance with the present invention, novel lactam derivatives are provided which are inhibitors of the enzyme Factor Xa and have the structure I 
including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein n is an integer from 1 to 5;
R1, R2 and R3 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, alkoxy, cyano, nitro, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl, 
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
or R1, R2 and R3 can in pairs of two join together to form a saturated carbocylic or heterocylic ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
or R1 and R2 can join together to form an unsaturated carbocylic or heterocylic ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5 wherein R3 is optionally a bond participating in the unsaturation of said ring;
R4, R6, R8, R9, Ra, Rb, are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl or polycycloalkynylalkyl; all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
R5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, aminocarbonyl, substituted aminocarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynyl-alkyl, cyano, nitro, hydroxy, amino, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94S(O)Ra, 
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
R7 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl, 
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
R10 and R10a are the same or different are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl polycycloalkynylalkyl, 
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
R11 and R12 are the same or different and are independently selected from hydrogen, alkyl, aryl, cyano, nitro, heteroaryl, sulfonyl, acyl, amido, sufonamido, sulfamoyl, alkoxycarbonyl, carboxy, xe2x80x94C(O)zRa, xe2x80x94S(O)zRa,
xe2x80x94P(O)(ORa)z where Z is 1 or 2, 
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
Rc is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl, 
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
Rd and Re are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, alkoxyalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl, hydroxyalkyl, alkoxycarbonyl, or aminocarbonyl; all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
or Rd and Re can be taken together with the nitrogen to which they are attached to form a cycloheteroalkyl ring or a heteroaryl ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4 , and Z5;
Z1, Z2, Z3, Z4 and Z5 are the same or different and are independently selected from hydrogen, halo, alkyl, haloalkyl, polyhaloalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, oxo, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, C(O)H, alkylcarbonyl, arylcarbonyl, amido, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, aminosulfinyl, aminosulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylsulfonyl, alkylsulfinyl, sulfonamido, sulfonyl, amidino, guanidino, 
and wherein
R4 and R5 can be taken together with the nitrogen to which they are attached to form a cycloheteroalkyl ring or a heteroaryl ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
R5 and R11 can be taken together to form a heteroaryl ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
R5 or R4 or R11 or R12 can form a ring with R6 which can be a cycloheteroalkyl or a heteroaryl ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
R10 or R10a can combine with R8 or R9 on an adjacent carbon atom to form a saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5;
R10 and R10a groups on adjacent carbon atoms can combine to form a saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z 2, Z3, Z4, and Z5;
R11 and R12 can combine to form a saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z1, Z2, Z3, Z4, and Z5.
Where one or more of R5, R4 or R6 are H, then double bond isomers are possible which are included in the present invention.
Preferred are compounds of formula I wherein n is 1 to 4, more preferably 3 or 4;
R1 and R2 are each independently hydrogen, halogen or alkyl.
R3 is selected from aryl (optionally substituted), 
where Rd and Re taken with the nitrogen to which they are attached form a 3 to 6-membered saturated ring (optionally substituted);
R6 and R7 are each H;
R8, R9, R10 and R10a are each hydrogen;
or R10 combines with one of R8, or R9 on an adjacent carbon atom, or combines with another R10 on an adjacent carbon atom to form an unsaturated carbocylic ring.
R4 is H or alkyl;
R5 is H, alkyl, aryl, arylalkyl, heteroaryl, cycloheteroalkyl, 
(any of which may be optionally substituted);
R11 and R12 are the same or different and are independently selected from hydrogen, carboxy, aryl, cyano, nitro, heteroaryl, xe2x80x94P(O)(ORa)2, xe2x80x94S(O)2Ra, xe2x80x94C(O)Ra, xe2x80x94C(O)ORa, 
or R11 and R12 combine to form a saturated or unstaturated carbocyclic or heterocyclic ring (optionally substituted);
Ra is hydrogen, aryl, alkyl, heteroaryl or cycloheteroalkyl (all optionally substituted);
Rb is hydrogen or alkyl; and configuration at the chiral center is (S)xe2x80x94 (as judged where R7 is H).
More preferred are compounds wherein
R3 is selected from phenyl (optionally substituted), 
where Ra is phenyl, phenylalkoxy, furyl, or thienyl (optionally substituted), and 
where Rd and Re taken with the nitrogen to which they are attached form a 5-membered saturated ring (optionally substituted);
R5 is
(a) aryl, arylalkyl, or heteroaryl (each optionally independently substituted, especially with one or more groups selected from halogen, alkyl, haloalkyl, hydroxyalkyl, acyl, alkoxy, haloalkoxy, cyano, amino, aryl, oxo, xe2x80x94C(NH)NH2, or xe2x80x94C(O)NH2);
(b) 
(especially where Ra is hydrogen or alkyl, and Rb is alkyl, aminocarbonyl, alkoxycarbonyl, aminocarbonylalkyl, carboxyalkyl, or hydroxyalkyl); and
(c) C(O)Ra, or C(O)ORa (especially where Ra is alkyl, alkenyl, hydroxyalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, any of which may be optionally substituted);
R11 and R12 are the same or different and are independently selected from hydrogen, nitro, carboxy, cyano, aryl, heteroaryl, xe2x80x94CO2Ra1, xe2x80x94SO2Ra1, xe2x80x94CONRd1Re1, and xe2x80x94C(O)Ra2 where Ra2 is alkyl, aryl or heteroaryl (each optionally substituted, preferrably with one or more alkoxy, alkyl or halogen), and Ra1 Rd1 and Re1 are independently selected from hydrogen, alkyl, alkoxyalkyl, aryl and heteroaryl);
or R11 and R12 combine to form an optionally substituted ring of formula 
where X and Y are independently selected from NRa and O (especially where the ring is substituted with one or more alkyl or oxo groups).
In addition, in accordance with the present invention, a method for preventing, inhibiting or treating cardiovascular diseases associated with thromboses is provided, wherein a compound of formula I is administered in a therapeutically effective amount which inhibits Factor Xa.